Topical foam composition

ABSTRACT

The present invention relates to a novel oil in water emulsion aerosol foam composition containing an active agent for the treatment of various chronic and acute skin conditions, particularly acne and psoriasis; and processes for preparing the emulsion aerosol foam compositions. In particular, the present invention relates to oil in water emulsion aerosol foam compositions containing a retinoid in the oil phase.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 12/711,337,filed 24 Feb. 2010, which claims the benefit of U.S. ProvisionalApplication No. 61/202,403, filed 25 Feb. 2009, which are incorporatedby reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to novel aerosol foam compositionscontaining a pharmaceutically active agent for the treatment of skindisease.

BACKGROUND OF THE INVENTION

There are many challenges in topical drug delivery. The topicalcomposition should deliver the active agent to the site of treatment,have desirable sensory characteristics, not leave an unpleasant residueon the surface of the skin, and not cause irritation or discomfort.Aerosol foams are known to be suitable for this purpose.

U.S. Pat. No. 7,387,807 to Callaghan et al. discloses a topicalcomposition comprising an extract of feverfew, pharmaceuticalexcipients, cosmetic agents, and other biologically active substances,such as retinoids. The composition may be in the form of an emulsionsuch as a cream or lotion.

U.S. Pat. No. 7,326,408 to Angel et al. discloses a composition for thetopical treatment of acne comprising one or more sunscreen agents and anantibacterial medication, where the composition may be in the form of agel, spray, foam, lotion or other form suitable for application to theskin. The composition may further comprise an additional anti-acnemedication, such as a retinoid (e.g. tretinoin, adapalene ortazarotene).

U.S. Pat. No. 6,730,288 to Abram describes an aerosol foam compositionincluding an effective amount of a pharmaceutically active ingredient,an occlusive agent, an aqueous solvent, an organic cosolvent, thepharmaceutically active ingredient being insoluble in both water and theocclusive agent, and the occlusive agent being present in an amountsufficient to form an occlusive layer on the skin, in use.

US published application No. 2006/0292080 to Abram et al. describes anoil in water emulsion foam comprising: a vitamin or analogue thereofsolubilized in the water phase and a stabilizer solubilized in the oilphase, an emulsifier, an occlusive agent, and an organic co-solvent, andno description of the particle size of the oil phase.

US published application No. 2006/0057168 to Larm et al. describes aprocess for the preparation of an oil in water microemulsion orsub-micron emulsion composition, in particular an oil in watermicroemulsion or sub-micron emulsion foam composition. These submicronor micro emulsion foams have a comparatively high oil content andrequire both a hydrophilic and a hydrophobic surfactant.

The present invention is directed to low oil and low surfactantsubmicron emulsions or microemulsion aerosol foams containing apharmaceutically active agent, which are cosmetically elegant,chemically and physically stable, well tolerated, easy to formulate, andsuitable for application to the face.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to an oil in water emulsion aerosolfoam composition having an oil phase and a water phase, said compositioncomprising a pharmaceutically active agent, water, oil, an oil miscibleorganic solvent, a surfactant, and a propellant. The present inventionprovides for a low oil and a low surfactant content in an oil in wateremulsion aerosol foam composition.

In one embodiment, the present invention provides an oil in wateremulsion aerosol foam composition comprising an oil phase and a waterphase, said composition comprising:

a pharmaceutically active agent,

water,

an oil present in an amount of less than about 10% by weight,

an oil miscible organic solvent,

a surfactant component comprising a hydrophilic surfactant, in an amountfrom about 0.1% to about 10% by weight, and

a propellant; and wherein the pharmaceutically active agent issolubilized in the oil phase of the composition, and wherein theparticle size of the oil phase is less than about 1000 nm.

According to another embodiment, the present invention provides aprocess for the preparation of an oil in water submicron or microemulsion aerosol foam composition, comprising a pharmaceutically activeagent, water, an oil present in an amount of less than about 10% byweight, an oil miscible organic solvent, a surfactant componentcomprising a hydrophilic surfactant in an amount from about 0.1% toabout 10% by weight, and a propellant, the process comprising:

-   -   a) admixing the pharmaceutically active agent, a first aliquot        of water, oil, oil miscible organic solvent and surfactant        component to form an oil in water emulsion,    -   b) heating the oil in water emulsion of step (a) to a phase        inversion temperature wherein the oil in water emulsion forms a        water in oil emulsion,    -   c) cooling the water in oil emulsion to below the phase        inversion temperature to form a submicron or micro oil in water        emulsion,    -   d) adding a second aliquot of water to cool the submicron or        micro oil in water emulsion,    -   e) actuating a sample of the submicron or micro oil in water        emulsion with a propellant to form an oil in water submicron or        micro emulsion aerosol foam.

According to an embodiment, the present invention provides a productproduced by this process.

According to a further embodiment, the present invention provides amethod of treating a skin disease, disorder or condition, comprisingadministering to the skin of a patient requiring such treatment aneffective amount of a composition of the present invention.

According to yet another embodiment, the present invention relates tothe use of the compositions described herein for the preparation of amedicament for the treatment of a skin disease, disorder or condition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic flow diagram showing one preferred embodiment ofthe present invention in which a low oil and low surfactant content, oilin water submicron or micro emulsion aerosol foam composition (730/2/1)is prepared. The method is described in detail in Example 1.

FIG. 2 shows the distribution of tazarotene within the epidermis afterapplication of tazarotene formulations of the present invention (706/8/2and 706/8/3) compared to commercially available tazarotene cream and gelformulations (i.e. TAZORAC® cream and gel).

FIG. 3 shows the distribution of tazarotene within the dermis afterapplication of tazarotene formulations of the present invention (706/8/2and 706/8/3) compared to commercially available tazarotene cream and gelformulations (i.e. TAZORAC® cream and gel).

FIG. 4 shows the compatibility of high HLB ethoxylated fatty alcoholether surfactant with tazarotene (tazarotene stability). A comparison ismade against various low HLB surfactants.

FIG. 5 shows the compatibility of high HLB ethoxylated fatty alcoholether surfactant with tazarotene (tazarotene sulfoxide formation). Acomparison is made against various low HLB surfactants.

FIG. 6 shows the particle size distribution of the oil phase of thepresent submicron or micro emulsions (730/2/1).

DETAILED DESCRIPTION

The present invention is directed to an oil in water emulsion aerosolfoam composition having an oil phase and a water phase, said compositioncomprising a pharmaceutically active agent, water, oil, an oil miscibleorganic solvent, a surfactant, and a propellant. In an embodiment, thepresent invention provides low oil and low surfactant content, oil inwater emulsion aerosol foam compositions. According to a furtherembodiment, the compositions are formulated as a submicron emulsion ormicroemulsion.

Thus, according to an embodiment, the present invention provides an oilin water emulsion aerosol foam composition comprising an oil phase and awater phase, said composition comprising:

a pharmaceutically active agent,

water,

an oil present in an amount of less than about 10% by weight,

an oil miscible organic solvent,

a surfactant component comprising a hydrophilic surfactant, in an amountfrom about 0.1% to about 10% by weight, and

a propellant; and wherein the pharmaceutically active agent issolubilized in the oil phase of the composition, and wherein theparticle size of the oil phase is less than about 1000 nm.

Together, the oil and oil miscible organic solvent comprise the oilphase of the composition, along with any oil miscible excipients.

According to an embodiment, the mean particle size of the oil phase isabout 100 nm.

In one embodiment, the present compositions are substantially free orfree from a water miscible organic solvent, such as propylene glycol.

In one alternative embodiment, the pharmaceutically active agent issolubilized in the water phase of the composition.

The characteristics of oil particles in their delivery ofpharmaceutically active agents across the skin barrier are summarised inTable 1 below:

TABLE 1 Particle size Description Characteristics <10,000 nm EmulsionBlue-white, milky liquid, reasonable physical stability. Particlesreside on skin surface → percutaneous delivery. 100-1000 nm  SubmicronBluish, translucent liquid. Enhanced emulsion physical stability.Particles reside on skin surface → enhanced percutaneous delivery. 10-100 nm Microemulsion Translucent-transparent liquid. Excellentphysical stability. Particles reside on skin surface → enhancedpercutaneous delivery.  1-100 nm Nanoemulsion Translucent-transparentliquid. Excellent physical stability. Particles reside on skin surface,within stratum corneum and in hair follicles → optimal percutaneousdelivery.

Oil Component

Suitably, the oil is present in the composition in an amount from about1% to about 9% by weight. In another embodiment the oil is present in anamount from about 3% to about 8% by weight, such as about 3%_(,)4%_(, 5)%_(,) 6%, 7% or 8% by weight.

The oil is in the discontinuous phase of the oil in water emulsionsystem. In an embodiment, the oil is a hydrocarbon. Suitably, thehydrocarbon is selected from an aromatic compound, or a linear, branchedor cyclic alkane or alkene, or mixtures thereof.

According to an embodiment, the aromatic compound is selected from thegroup consisting of azulene, chamazulene andcyclohexylidene-diphenylmethane, and mixtures thereof.

According to a further embodiment, the linear, branched or cyclic alkaneor alkene is selected from the group consisting of isoparaffin,didecene, diethylhexylcyclohexane, eicosane, isododecane, isoeicosane,isohexadecane, longifolene, mineral oil, paraffin, pentahydrosqualene,petrolatum, squalane, squalene, tetradecene, derivatives theoreof, andmixtures thereof.

According to an embodiment, the oil is mineral oil. In one embodiment,the mineral oil is present in an amount from about 1% to about 9% byweight. In another embodiment the mineral oil is present in about 3% toabout 8% by weight, such as about 3%, 4%, 5%, 6%, 7% or 8% by weight.

In another embodiment, the oil is a vegetable oil. Suitably, thevegetable oil is selected from palm oil, soybean oil, rapeseed oil,sunflower oil, peanut oil, corn oil, olive oil, coconut oil, cottonseedoil, linseed oil, grapeseed oil, hazelnut oil or sesame oil, andmixtures thereof.

Surfactant Component

The present topical foam compositions comprise a surfactant component.Suitably, the surfactant is present in the composition in an amount fromabout 1% to about 8% by weight. In another embodiment the surfactant ispresent in an amount from about 2% to about 6% by weight, such as about2%, 3%, 4%, 5% or 6% by weight.

A surfactant's hydrophilic/lipophilic balance (HLB) describes thesurfactant's affinity toward water or oil. The HLB scale ranges from 1(totally lipophilic) to 20 (totally hydrophilic), with 10 representingan equal balance of both characteristics. Lipophilic surfactants tend toform water-in-oil (w/o) emulsions, and hydrophilic surfactants tend toform oil-in-water (o/w) emulsions. The HLB of a blend of two surfactantsequals the weight fraction of surfactant A times its HLB value plus theweight fraction of surfactant B times its HLB value (weighted average).

In one embodiment the surfactant component comprises a hydrophilicsurfactant. In an another embodiment, the surfactant component consistsof a single hydrophilic surfactant, and in another embodiment, thesurfactant component comprises more than one surfactant and the weightedaverage of their HLB values is between about 10 and about 20. In anotherembodiment, the surfactant component consists of non-ionic surfactants.

Suitable non-ionic surfactants include but are not limited toethoxylated fatty alcohol ethers, PEG derivatives, ethoxylated fattyacids, propylene glycol esters, fatty alcohols, glycerol esters andderivatives, polymeric ethers and sorbitan esters, and mixtures thereof.

Exemplary ethoxylated fatty alcohol ethers include steareth-2,steareth-10, steareth-20, ceteareth-2, ceteareth-3, ceteareth-5,ceteareth-6, ceteareth-10, ceteareth-12, ceteareth-15, ceteareth-20,ceteareth-21, ceteareth-22, ceteareth-25, ceteareth-30, ceteareth-31,ceteareth-32, ceteareth-33, laureth-3, laureth-4, laureth-5, laureth-9,laureth-10, laureth-12, laureth-15, laureth-20, laureth-21, laureth-22,laureth-23, nonoxynol-9, oleth-2, oleth-5, oleth-10 and oleth-20.

In one embodiment the hydrophilic ethoxylated fatty alcohol ether isselected from the group consisting of steareth-10, steareth-20,ceteareth-10, ceteareth-12, ceteareth-15, ceteareth-20, ceteareth-21,ceteareth-22, ceteareth-25, ceteareth-30, ceteareth-31, ceteareth-32,ceteareth-33, ceteareth-6, laureth-5, laureth-9, laureth-10, laureth-12,laureth-15, laureth-20, laureth-21, laureth-22, laureth-23, nonoxynol-9,oleth-10 and oleth-20.

In another embodiment the wherein the hydrophilic ethoxylated fattyalcohol ether is Macrogol Cetostearyl Ether 12 (ceteareth-12). In oneembodiment the Macrogol Cetostearyl Ether 12 is present in thecomposition in an amount from about 1% to about 8% by weight. In anotherembodiment the Macrogol Cetostearyl Ether 12 is present in an amountfrom about 2% to about 6% by weight, such as about 2%, 3%, 4%, 5% or 6%by weight.

Exemplary PEG derivatives include PEG-7 hydrogenated castor oil, PEG-25hydrogenated castor oil, PEG-30 castor oil, PEG-31 castor oil, PEG-32castor oil, PEG-33 castor oil, PEG-34 castor oil, PEG-35 castor oil,PEG-40 hydrogenated castor oil, PEG-50 castor oil and PEG-60hydrogenated castor oil.

Exemplary ethoxylated fatty acids include PEG-5 oleate, PEG-6 oleate,PEG-10 oleate, PEG-6 stearate, PEG-8 stearate and PEG-9 stearate, PEG-20stearate, PEG-40 stearate, PEG-41 stearate, PEG-42 stearate, PEG-43stearate, PEG-44 stearate, PEG-45 stearate, PEG-46 stearate, PEG-47stearate, PEG-48 stearate, PEG-49 stearate, PEG-50 stearate and PEG-100stearate.

Exemplary propylene glycol esters include propylene glycol palmitate andpropylene glycol stearate.

Exemplary fatty alcohols include cetyl alcohol and stearyl alcohol.

Exemplary glyceryl esters and derivatives include glyceryl behenate,glyceryl dibehenate, glyceryl dioleate, glyceryl distearate, glyceryllinoleate, glyceryl oleate, glyceryl stearate, PEG-23 glyceryl cocoate,PEG-6 caprylic/capric glycerides, PEG-7 glyceryl cocoate,polyglyceryl-10 diisostearate, polyglyceryl-2 diisostearate,polyglyceryl-3 diisostearate and polyglyceryl-6 diisostearate.

Exemplary polymeric ethers include poloxamer 124, poloxamer 182,poloxamer 184, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer338 and poloxamer 407.

Exemplary sorbitan derivatives include polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, sorbitan laurate, sorbitan oleate,sorbitan palmitate, sorbitan sesquioleate, sorbitan stearate andsorbitan trioleate.

In one embodiment, the surfactant component comprises one or morehydrophilic non-ionic surfactants and is substantially free, or free oflipophilic surfactant. According to an embodiment, the surfactantcomponent is substantially free, or free of fatty alcohol.

In one embodiment, the surfactant component comprises a hydrophilicethoxylated fatty alcohol ether. In another embodiment, the surfactantcomponent comprises a hydrophilic ethoxylated fatty alcohol ether and issubstantially free, or free of lipophilic surfactant.

Pharmaceutical Active Agent

Suitably, the pharmaceutically acceptable active agent for use in thecompositions herein is selected from retinoids, retinoic acid metabolicblocking agents (RAMBAs), immune response modifier compounds, vitamin Danalogues, corticosteroids, antihistamines, antibacterial agents,antifungal agents, antiviral agents, cytotoxic agents, psoralens,antialopecia agents, anti-androgens, antipruritic agents, keratolyticagents, tars, dithranol, antiseptics, sunscreens, anaesthetics,analgesics, skin conditioning agents and nutritional agents, saltsthereof, derivatives thereof and mixtures thereof. In one embodiment,the compositions may comprise more than one pharmaceutically activeagent, salt or derivative thereof. Suitable concentration ranges for thepharmaceutically active agent range from about 0.001% to about 30% byweight, depending on the nature of the active agent or combination ofactive agents.

In one embodiment, the pharmaceutically active agent is a retinoid.Examples of suitable retinoids include, but are not limited to,tazarotene, tretinoin, isotretinoin, acitretin, etretinate, adapalene,bexarotene, alitretinoin, retinol, retinal, retinyl palmitate, retinylacetate, retinyl propionate, retinyl linoleate, ethyl5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)thiophene-2-carboxylate,6-(2-4,4-dimethylthiochroman-6-yl)-ethynyl)-3-pyridylmethanol and6-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl) pyridine-3-carbaldehyde,salts thereof, derivatives thereof and mixtures thereof. In oneembodiment, the retinoid is tazarotene. In an alternative embodiment,the retinoid is tretinoin. In another embodiment, the compositioncomprises a retinoid in combination with a second pharmaceuticallyactive agent. In one embodiment the combination is tazarotene and asecond pharmaceutically active agent. In another embodiment thecombination is tretinoin and a second pharmaceutically active agent.

Suitably, one combination of the retinoid is with a corticosteroid, suchas clobetasol propionate; or in combination with a vitamin D analoguesuch as calcipotriene; or in combination with an antibacterial such asclindamycin or a pharmaceutically acceptable salt thereof (e.g.clindamycin phosphate). Alternatively, in an embodiment, the presentcompositions comprise tretinoin in combination with an antibacterialagent, such as clindamycin or a pharmaceutically acceptable salt thereof(e.g. clindamycin phosphate).

Suitable concentration ranges for the retinoid in the compositioninclude, for example, about 0.001% to about 5% by weight. In oneembodiment the retinoid is present in an amount from about 0.01% toabout 1%. In another embodiment the retinoid is present in an amountfrom about 0.025% to about 0.5%. In one embodiment when the retinoid istazarotene, it is present in an amount from about 0.05% or 0.1% byweight. In another embodiment when the retinoid is tretinoin, it ispresent in an amount from about 0.025%, 0.05% or 0.1%.

A suitable retinoic acid metabolic blocking agents (RAMBAs) for useherein as a pharmaceutically acceptable active agent is rambazole.

Suitable immune response modifier compounds, immunosuppressant agents,immunoregulating agents and immunomodulators for use herein includechemically or biologically-derived agents that modify the immuneresponse or the functioning of the immune system (by the stimulation ofantibody formation or the inhibition of white blood cell activity).Exemplary agents or compounds include, but are not limited to cyclicpeptides (such as cyclosporine), tacrolimus, tresperimus, pimecrolimus,sirolimius (rapamycin), verolimus, laflunimus, laquinimod, mycophenolicacid, and imidazoquinoline amines such as imiquimod, salts thereof,derivatives thereof, and mixtures thereof.

Suitable vitamin D analogues include, but are not limited to, calcidiol,calcitriol, calcipotriene, paricalcitol, 22-oxacolcitriol,dihydrotachysterol, calciferol, salts thereof, derivatives thereof, andmixtures thereof.

Suitable corticosteroids include, but are not limited to, alclometasonedipropionate, amcinonide, beclomethasone dipropionate, betamethasonebenzoate, betamethasone dipropionate, betamethasone valerate,budesonide, clobetasol propionate, clobetasone butyrate, cortisoneacetate, desonide, desoximetasone, diflorasone diacetate, diflucortolonevalerate, fluclorolone acetonide, flumethasone pivalate, fluocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone, fluprednideneacetate, flurandrenolide, flurandrenolone, fluticasone propionate,halcinonide, halobetasol propionate, hydrocortisone, hydrocortisoneacetate, hydrocortisone butyrate, hydrocortisone propionate,hydrocortisone valerate, methylprednisolone acetate, mometasone furoate,pramoxine hydrochloride, prednisone acetate, prednisone valerate,triamcinolone acetonide, prednicarbate, salts thereof, derivativesthereof, and mixtures thereof.

Suitable antihistamines include, but are not limited to, cetirizine,vapitadine, diphenhydramine, triprolidine, pyrilamine, chlorcyclizine,promethazine, carbinoxamine, tripelennamine, brompheniramine,hydroxyzine, terfenadine, chlorpheniramine, salts thereof, derivativesthereof, and mixtures thereof.

Suitable antibacterial agents include, but are not limited to,gentamicin, neomycin, streptomycin, cefpodoxime proxetil, clindamycin,lincomycin, erythromycin, bacitracin, gramicidin(s), vancomycin,doxycycline, minocycline, oxytetracycline, tetracycline, fosfomycin,fusidic acid, mupirocin, sulfacetamide, metronidazole and dapsone, saltsthereof, derivatives thereof, and mixtures thereof.

Suitable antifungal agents include, but are not limited to, thoseselected from the group consisting of echinocandins such asanidulafunin, caspofungin and micafungin; polyenes such as amphotericinB, candicidin, filipin, fungichromin, hachimycin, hamycin, lucensomycin,mepartricin, natamycin, nystatin, pecilocin, perimycin; allylamines suchas butenafine, naftifine and terbinafine; imidazoles such as bifonazole,butoconazole, chlormidazole, cloconazole, clotrimazole, econazole,enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole,lanoconazole, miconazole, neticonazole, omoconazole, oxiconazolenitrate, sertaconazole, sulconazole and tioconazole; thiocarbamates suchas liranaftate, tolciclate, tolindate and tolnafate; triazoles such asalbaconazole, fluconazole, itraconazole, posaconazole, ravuconazole,saperconazole, terconazole and voriconazole; and other antifungal agentssuch as acrisorcin, amorolfine, biphenamine, bromosalicylchloranilide,buclosamide, calcium propionate, chlorphenesin, ciclopirox, cloxyquin,coparaffinate, exalamide, flucytosine, haloprogin, hexetidine,loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione,salicylanilide, sodium propionate, sulbentine, tenonitrozole, triacetin,undecylenic acid, zinc propionate, griseofulvin, oligomycins,pyrroInitrin, siccanin, viridian, salts thereof, derivatives thereof,and mixtures thereof.

Suitable antivirals include, but are not limited to, acyclovir,desciclovir, carbovir, famciclovir, foscarnet sodium, ganciclovir,interferons, penciclovir, valaciclovir, salts thereof, derivativesthereof, and mixtures thereof.

Suitable cytotoxic agents include, but are not limited to, azathioprine,cyclophosphamide, cyclosporine, methotrexate, hydroxyurea, thalidomide,bleomycin, fluorouracil, salts thereof, derivatives thereof, andmixtures thereof.

An exemplary psoralen is methoxsalen.

Suitable anti-androgens include, but are not limited to, spironolactone,cyproterone, flutamide, finasteride, salts thereof, derivatives thereof,and mixtures thereof.

An exemplary antialopecia agent is minoxidil.

Suitable antipruritics include, but are not limited to, calamine,camphor and menthol, salts thereof, derivatives thereof, and mixturesthereof.

Suitable keratolytic agents include, but are not limited to, benzoylperoxide, salicylic acid, urea, resorcinol, sulphur, salts thereof,derivatives thereof, and mixtures thereof.

Suitable tars include, but are not limited to, coal tar, pine tar, woodtar, salts thereof, derivatives thereof, and mixtures thereof.

Suitable antiseptics include, but are not limited to, hydrogen peroxide,chlorhexidine, cetrimide, povidone iodine, triclosan, salts thereof,derivatives thereof, and mixtures thereof.

Suitable sunscreens include, but are not limited to, aminobenzoic acid,avobenzone, bemotrizinol, bisoctrizole, β-carotene, cinoxate,4-(dimethylamino)benzoic acid, dioxybenzone, drometrizole, ecamsule,ensulizole, ethylhexyl triazone, homosalate, lawsone, menthylanthranilate, 4-methylbenzylidene camphor, mexenone, octabenzone,octocrylene, octyl methoxycinnamate, octyl salicylate, oxybenzone,sulisobenzone, zinc oxide, titanium dioxide, salts thereof, derivativesthereof, and mixtures thereof.

Suitable anaesthetics and analgesics include, but are not limited to,benzocaine, lidocaine, prilocalne and choline salicylate, salts thereof,derivatives thereof, and mixtures thereof.

Suitable skin-conditioning agents include, but are not limited to,hydrocarbon oils and waxes, silicones, fatty acid derivatives,cholesterol, di- and tri-glycerides, vegetable oils, acetoglycerideesters, alkyl esters, alkenyl esters, lanolin, milk tri-glycerides, waxesters, beeswax, sterols, phospholipids, derivatives thereof, andmixtures thereof.

Exemplary nutritional agents include vitamins, essential amino acids,essential fats, antioxidants, salts thereof, derivatives thereof, andmixtures thereof.

Water Phase

The topical foam compositions of the present invention also comprisewater. Water forms the continuous phase of the emulsion system. In anembodiment, the foam compositions comprise water in an amount from about65% to about 90% by weight. In another embodiment the water is presentin an amount from about 70% to about 85% by weight. In anotherembodiment the water is present at about 77% by weight.

Oil Miscible Organic Solvent

The present topical foam compositions comprise an oil miscible organicsolvent to facilitate solubilisation of the active agent in the oil.Together, the oil miscible organic solvent and oil comprise the oilphase of the composition.

The oil miscible organic solvent is present in the composition in anamount from about 1% to about 20% by weight. In one embodiment the oilmiscible organic solvent is present in an amount from about 3% to about15% by weight. In another embodiment the oil miscible organic solvent ispresent in an amount of about 5% by weight.

Suitable, non-limiting examples of oil miscible organic solvents includealcohols such as caprylic alcohol, decyl alcohol, dodecylhexadecanol,dodecyltetradecanol, hexyl alcohol, hexyldecanol, hexyldecyloctadecanol,isocetyl alcohol, isostearyl alcohol, lauryl alcohol, myristyl alcohol,octyldecanol, octyldodecanol, oleyl alcohol, tridecyl alcohol; esterssuch as butyl stearate, C12-15 alkyl benzoate, C12-15 alkyl lactate,caprylic/capric triglyceride, cetearyl ethylhexanoate, cetearylisononanoate, cetyl octanoate, cetyl palmitate, coco-caprylate/caprate,cocoglycerides, decyl oleate, dibutyl adipate, dicaprylyl carbonate,diethylhexyl adipate, di-ethylhexyl succinate, diisopropyl adipate,dioctyl malate, di-PPG-2 myreth-10 adipate, di-PPG-3 myristyl etheradipate, ethyl oleate, ethylhexyl cocoate, ethylhexyl hydroxystearate,ethylhexyl palmitate, ethylhexyl pelargonate, ethylhexyl stearate, hexyllaurate, hexyldecyl laurate, hexyldecyl stearate, isocetyl stearate,isocetyl stearoyl stearate, isodecyl oleate, isopropyl myristate,isopropyl palmitate, isostearyl neopentanoate, isotridecyl isononanoate,lauryl lactate, myristyl lactate, myristyl myristate, octyldodecylstearoyl stearate, oleyl erucate, oleyl oleate, pentaerythrityltetracaprylate/caprate, pentaerythrityl tetraisostearate, PPG-2 myristylether propionate, propylene glycol dicaprylate/dicaprate, propyleneglycol isostearate, propylheptyl caprylate, stearyl octanoate; etherssuch as dicaprylyl ether, PPG-10 cetyl ether, PPG-11 stearyl ether,PPG-14 butyl ether, PPG-15 stearyl ether, PPG-3 hydrogenated castor oil,PPG-3 myristyl ether; carboxylic acids such as C10-40 hydroxyalkyl acid,C10-40 isoalkyl acid, C32-36 isoalkyl acid, capric acid, caproic acid,caprylic acid, coconut acid, lauric acid, linoleic acid, linolenic acid,linseed acid, myristic acid, oleic acid, ricinoleic acid and lanolin.

According to an embodiment, the oil miscible organic solvent is selectedfrom the group consisting of diisopropyl adipate, isopropyl myristate,dodecanol and caprylic/capric triglycerides.

In one embodiment, the oil miscible organic solvent is diisopropyladipate (also referred to herein as DIPA). In one embodiment the DIPA ispresent in the composition in an amount from about 1% to about 20% byweight. In another embodiment the DIPA is present in an amount fromabout 3% to about 15% by weight. In another embodiment the DIPA ispresent in an amount of about 5% by weight.

According to a further embodiment, the present compositions comprise asecond pharmaceutically acceptable active agent. In one embodiment, thesecond active agent is solubilized in the water phase (i.e. thecontinuous phase). This may be achieved by dissolving the second activeagent in an aliquot of water or an aliquot of a water miscible organicsolvent, and subsequently solubilising the aliquot in the composition.

According to an embodiment, the water miscible organic solvent ispresent in an amount from about 1% to about 20% by weight. According toa further embodiment, the water miscible organic solvent is present inan amount of about 10% by weight.

Suitably, water miscible organic solvents include, but are not limitedto, alcohols, including amyl alcohol, benzyl alcohol,cyclohexanedimethanol, diacetone alcohol, ethyl alcohol, hexyl alcohol,isobutyl alcohol, isopropyl alcohol, methyl alcohol, n-butyl alcohol,propyl alcohol, t-butyl alcohol, tetrahydrofurfuryl alcohol; carboxylicacids, including acetic acid; diols, including 1,2-hexanediol, butyleneglycol, diethylene glycol, dipropylene glycol, ethyl hexanediol,ethylene glycol, hexylene glycol, pentylene glycol, propylene glycol,tetraethylene glycol, triethylene glycol, tripropylene glycol; andpolyols including polyethylene glycol, butanetriol, glycerol and1,2,6-hexanetriol.

In one embodiment, the water miscible organic solvent is propyleneglycol.

Propellant

It is recognized that the present topical foam compositions must utilizea propellant in order to produce the foam upon application. Thepropellant may be any suitable liquefied gas or mixture thereof, such asa hydrocarbon, a chlorofluorocarbon, dimethyl ether, hydrofluorocarbonsand a mixture thereof.

Other suitable propellants include compressed gases such as nitrogen,carbon dioxide, nitrous oxide and air. In a preferred embodiment, thepropellant is a mixture of hydrocarbons. In a further preferredembodiment, the mixture of hydrocarbons is a mixture of propane,n-butane and isobutane.

The propellant is present in an amount from about 1% to about 20% byweight, or about 3% to about 15% by weight. In one embodiment, thepropellant is present in an amount from about 5% to about 10% by weight,such as about 5%, 6%, 7%, 8%, 9% or 10% by weight. The propellant may beintroduced into the composition at the time of filling, utilizing apressurized container such as a standard aerosol dispenser.

When the composition is released from the pressurized container, thecomposition is an aerosol foam (also known as a mousse). According toone embodiment, the aerosol foam is homogeneous. In another embodiment,the aerosol foam breaks easily with shear, such as gentle mechanicalaction e.g. rubbing or spreading.

In another embodiment the propellant is absent from the composition.According to such an embodiment, the composition may be expelled fromits container by mechanical means, such as by a pump action or asqueezing action on the container.

Suitable pressurized containers for use herein include aluminium,tin-plate and glass containers.

In one embodiment, the pressurized container is a one-piece aluminiumcontainer in which the inner surface is lined with a chemically inertlining. One suitable inner surface lining for use herein ispolyamide-imide (PAM), such as that supplied by Exal Corporation, ofYoungstown, Ohio. The container may be fitted with an upright-use orinverted-use valve and a conventional foam spout actuator.Alternatively, the container may be fitted with a metered-dose valve.

Dermatologically Acceptable Excipients

According to an embodiment, the compositions may further comprise one ormore dermatologically acceptable excipients. Non-limiting examples ofsuch dermatologically acceptable excipients include diluents, suspendingagents, adjuvants, preservatives, colorants, emollients, pH adjustingagents (including buffers), thickeners, humectants, fragrances,stabilizers, chelating agents, anticaking agents, viscosity increasingagents, solubilizers, plasticizers, penetration enhancing agents, filmforming agents, antioxidants, wetting agents, foam boosters or anymixture of these components.

In one embodiment, the one or more dermatologically acceptableexcipients comprise a preservative, an antioxidant and a pH adjustingagent.

Preservative

The present topical aerosol foam compositions may additionally comprisea preservative. The preservative is present in the composition in anamount from about 0.01% to about 2% by weight. In one embodiment thepreservative is present in an amount from about 0.1% to about 1% byweight. In another embodiment the preservative is present in an amountof about 0.3% by weight.

Suitable preservatives include, but are not limited to benzyl alcohol,diazolidinyl urea, methyl paraben, ethyl paraben, propyl paraben, butylparaben, phenoxyethanol, sorbic acid and salts thereof such as potassiumsorbate, benzoic acid and salts thereof such as sodium benzoate, andmixtures thereof.

According to an embodiment, the preservative is a combination of sorbicacid and potassium sorbate.

Antioxidant

The present topical aerosol foam compositions may further comprise anantioxidant. The antioxidant is present in the composition in an amountfrom about 0.001% to about 1% by weight. In one embodiment theantioxidant is present from about 0.05% to about 0.5% by weight. Inanother embodiment the antioxidant is present in an amount of about 0.1%by weight.

Suitable antioxidants include, but are not limited to, butylatedhydroxytoluene (BHT), butylated hydroxyanisole, tocopherol, propylgallate, vitamin E TPGS, derivatives thereof, and mixtures thereof. Inone embodiment, the antioxidant is BHT.

pH Adjusting Agent

The present topical aerosol foam compositions may further comprise a pHadjusting agent to aid in stabilizing the active agent. According to anembodiment, the pH adjusting agent is present in an amount from about0.01% to about 10% by weight. In one embodiment, the pH adjusting agentis a base. Suitable pH adjusting bases include but are not limited tobicarbonates, carbonates and hydroxides (such as alkali or alkalineearth metal hydroxides, as well as transition metal hydroxides). The pHadjusting agent may also be an acid, an acid salt, or mixtures thereof.The pH adjusting agent may also be a buffer. Suitable buffers include,but are not limited to citrate/citric acid, acetate/acetic acid,phosphate/phosphoric acid, formate/formic acid, propionate/propionicacid, lactate/lactic acid, carbonate/carbonic acid, ammonium/ammonia,edentate/edetic acid, derivatives thereof, and combinations thereof.According to an embodiment, the pH adjusting agent is a citrate/citricacid buffer. According to an embodiment, the citrate/citric acid bufferis present in an amount from about 0.02% to about 2% by weight.

In another embodiment, the present invention relates to an oil in wateremulsion aerosol foam composition comprising: tazarotene, water, an oilin an amount from about 3% to about 8% by weight, an oil miscibleorganic solvent, a surfactant component comprising a non-ionichydrophilic surfactant in an amount from about 2% to about 6% by weight,and a hydrocarbon propellant, wherein the tazarotene is solubilized inthe oil phase of the composition and wherein the particle size of theoil phase is less than about 1000 nm.

According to an embodiment, the mean particle size of the oil phase ofthe tazarotene aerosol foam is about 100 nm.

The tazarotene foam formulation exemplified by these embodiments isparticularly suited for application to small regions of the face for thetreatment of acne. In one embodiment, the tazarotene aerosol foamformulation is dispensed from a metered dose actuator. In anotheralternative embodiment, the tazarotene aerosol foam composition isformulated as a macro emulsion (i.e. the particle size of the oil phaseis greater than 1000 nm).

In another embodiment, a second pharmaceutically active agent issolubilized in the composition. In another embodiment the secondpharmaceutically active agent is solubilized in the water phase of thecomposition. This may be achieved by dissolving the furtherpharmaceutically active agent in an aliquot of water which issubsequently solubilized in the composition. Alternatively, the secondpharmaceutically active agent is dissolved in an aliquot of watermiscible organic solvent which is subsequently solubilized in thecomposition. In another embodiment the second pharmaceutically activeagent is in a composition comprising the retinoid tazarotene.

DEFINITIONS

As used herein, the terms “administering” and “administered,” refer toany method which delivers the composition to a subject in such a manneras to provide a therapeutic effect.

As used herein, the term “derivative(s) thereof” refers to prodrugs,solvates, hydrates, esters and acids of the pharmaceutically activeagent.

As used herein, the phrase an “effective amount” of an active agent oringredient, or pharmaceutically active agent or ingredient, which aresynonymous herein, refers to an amount of the pharmaceutically activeagent sufficient to have a therapeutic effect upon administration. Aneffective amount of the active agent may, will, or is expected to causerelief of symptoms. Effective amounts of the active agent will vary withthe particular disease or diseases being treated, the severity of thedisease, the duration of the treatment, and the specific components ofthe composition being used.

As used herein, the term “fatty alcohol” refers to an alcohol having analiphatic chain from about 9 to about 22 carbon atoms long.

As used herein, an “emulsion” refers to a mixture of two or moreimmiscible (unblendable) liquids wherein the particle size of thedispersed phase (i.e. oil in the case of an oil in water emulsion) isless than about 10,000 nm.

As used herein, a “submicron emulsion” refers to a mixture of two ormore immiscible (unblendable) liquids wherein the particle size of thedispersed phase (i.e. oil in the case of an oil in water emulsion) is inthe range from about 100 nm to about 1000 nm.

As used herein, a “microemulsion” refers to a mixture of two or moreimmiscible (unblendable) liquids wherein the particle size of thedispersed phase (i.e. oil in the case of an oil in water emulsion) is inthe range from about 10 nm to about 100 nm.

As used herein, “nanoemulsion” refers to a mixture of two or moreimmiscible (unblendable) liquids wherein the particle size of thedispersed phase (i.e. oil in the case of an oil in water emulsion) is inthe range from about 1 nm to 100 nm.

As used herein, the term “phase inversion temperature” refers to atemperature where an oil in water emulsion inverts to a water in oilemulsion (or vice versa).

As used herein, a “pH adjusting agent” refers to a specific pH adjustingagent or agents, including but not limited to, a buffer, a base or anacid, salts thereof and mixtures thereof, added to a composition.

The phrase “dermatologically acceptable excipient” as used herein refersto any inactive ingredient present in the herein described compositions.

As used herein, the phrase “pharmaceutically acceptable salts” refers tosalts that are pharmaceutically acceptable and that possess the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with acids such as, for example, aceticacid, benzoic acid, citric acid, gluconic acid, glutamic acid, glutaricacid, glycolic acid, hydrochloric acid, lactic acid, maleic acid, malicacid, malonic acid, mandelic acid, phosphoric acid, propionic acid,sorbic acid, succinic acid, sulfuric acid, tartaric acid, naturally andsynthetically derived amino acids, and mixtures thereof; or (2) saltsformed when an acidic proton present in the parent compound is either(i) replaced by a metal ion e.g. an alkali metal ion, an alkaline earthmetal ion, or an aluminium ion; or (ii) protonates an organic base suchas, for example, ethanolamine, diethanolamine, triethanolamine,tromethamine and N-methylglucamine.

As used herein, a “subject”, “individual” or “patient” refers to anysubject, particularly a human, for whom therapy is desired.

As used herein, a “treatment” or “treating” of a disease, disorder orcondition encompasses alleviation of at least one symptom thereof, areduction in the severity thereof, or the delay, prevention orinhibition of the progression thereof. Treatment need not mean that thedisease, disorder or condition is totally cured. A useful compositionherein need only to reduce the severity of a disease, disorder orcondition, reduce the severity of symptoms associated therewith, provideimprovement to a patient's quality of life, or delay, prevent or inhibitthe onset of a disease, disorder or condition.

Any concentration range, percentage range or ratio range recited hereinis to be understood to include concentrations, percentages or ratios ofany integer within that range and fractions thereof, such as one tenthand one hundredth of an integer, unless otherwise indicated.

It should be understood that the terms “a” and “an” as used above andelsewhere herein refer to “one or more” of the enumerated components. Itwill be clear to one of ordinary skill in the art that the use of thesingular includes the plural unless specifically stated otherwise.Therefore, the terms “a,” “an” and “at least one” are usedinterchangeably in this application.

Throughout the application, descriptions of various embodiments use“comprising” language, however in some specific instances, an embodimentcan alternatively be described using the language “consistingessentially of” or “consisting of”.

For the purposes of better understanding the present teachings and in noway limiting their scope, unless otherwise indicated, all numbersexpressing quantities, percentages or proportions, and other numericalvalues used in the specification and claims, are to be understood asbeing modified in all instances by the term “about.”

As used herein, the term “substantially free” of a specified componentrefers to a composition with less than about 1% of the specifiedcomponent.

Other terms used herein are intended to be defined by their well-knownmeanings in the art.

Process of Preparation

In one embodiment, the present invention provides a process for thepreparation of an oil in water submicron or micro emulsion aerosol foamcomposition, comprising a pharmaceutically active agent, water, an oilpresent in an amount of less than about 10% by weight, an oil miscibleorganic solvent, a surfactant component comprising a hydrophilicsurfactant in an amount from about 0.1% to about 10% by weight, and apropellant, the process comprising:

-   -   a) admixing the pharmaceutically active agent, a first aliquot        of water, oil, oil miscible organic solvent and surfactant        component to form an oil in water emulsion,    -   b) heating the oil in water emulsion of step (a) to a phase        inversion temperature wherein the oil in water emulsion forms a        water in oil emulsion,    -   c) cooling the water in oil emulsion to below the phase        inversion temperature to form a submicron or micro oil in water        emulsion,    -   d) adding a second aliquot of water to cool the submicron or        micro oil in water emulsion,    -   e) actuating a sample of the submicron or micro oil in water        emulsion with a propellant to form an oil in water submicron or        micro emulsion aerosol foam.

According to an embodiment, the first aliquot of water comprises about10% to about 40% by weight of the total water content of the submicronor micro oil in water emulsion aerosol foam and the second aliquot ofwater comprises about 90% to about 60% by weight of the total watercontent of the submicron or micro oil in water emulsion aerosol foam.

According to an embodiment, the first aliquot of water comprises about10% to about 40% by weight of the total water content of the submicronor micro oil in water emulsion aerosol foam and the second aliquot ofwater comprises about 90% to about 60% by weight of the total watercontent of the submicron or micro oil in water emulsion aerosol foam.

According to another embodiment, the first aliquot of water comprisesabout 15% to about 35% of the total water content of the submicron ormicro oil in water emulsion aerosol foam and the second aliquot of watercomprises about 85% to about 65% of the total water content of thesubmicron or micro oil in water emulsion aerosol foam.

According to a further embodiment, the first aliquot of water comprisesabout 20% to about 30% of the total water content of the submicron ormicro oil in water emulsion aerosol foam and the second aliquot of watercomprises about 80% to about 70% of the total water content of thesubmicron or micro oil in water emulsion aerosol foam.

According to yet a further embodiment, the first aliquot of watercomprises about 25% of the total water content of the submicron or microoil in water emulsion aerosol foam and the second aliquot of watercomprises about 75% of the total water content of the submicron or microoil in water emulsion aerosol foam.

The presently described process provides for the preparation of a lowoil and low surfactant submicron or micro emulsion aerosol foam, where aconcentrated submicron or micro emulsion is prepared (comprising thefirst aliquot of water) and is subsequently diluted (with the secondaliquot of water) to ultimately afford the desired low oil and lowsurfactant submicron or micro emulsion. By initially preparing aconcentrated submicron or micro emulsion, a sufficient concentration ofsurfactant is present in the composition to stabilize the submicron ormicro sized oil phase. The dilution step then provides the desired lowoil and low surfactant submicron or micro emulsion. It is thought thatthe addition of the second aliquot of water (which is at a temperaturesubstantially below the phase inversion temperature) serves to fix thesubmicron or micro emulsion structure of the composition and, of course,dilutes the composition to provide the low oil and low surfactantcomposition.

According to an embodiment, a second pharmaceutically active agent issolubilized in the water phase of the composition. This may be achievedby dissolving the second pharmaceutically active agent in an aliquot ofwater or water miscible organic solvent, which is subsequentlysolubilized in the composition.

In one embodiment, the second pharmaceutically active agent dissolved inan aliquot of water or water miscible organic solvent is added to thesubmicron or micro oil in water emulsion following step (d)). That is,the second pharmaceutically active agent is solubilized in the waterphase of the composition after formation of the submicron or microemulsion.

Another aspect of the invention is the product produced by this process.

Methods of Treatment

The emulsion aerosol foam compositions of the present invention arecosmetically elegant and suitable for application to the face fortreating a skin disorder or condition. The compositions are easilyspread, non-greasy, non-drying and leave minimal residue on the skin.

The present invention provides for a method of treating a skin disease,disorder or condition, comprising administering to the skin of a patientrequiring such treatment an effective amount of a composition of thepresent invention. In one embodiment, the skin disease, disorder orcondition is acne. In another embodiment, the skin disease, disorder orcondition is psoriasis.

The present invention also relates to the use of the compositions asdescribed herein for the preparation of a medicament for the treatmentof a skin disease, disorder or condition.

The present invention also relates to a method of treating a skindisease, disorder or condition by administering to the skin of a patientrequiring such treatment an effective amount of a composition of thepresent invention.

Exemplary, non-limiting, skin diseases, disorders or conditionstreatable by the present compositions include acne, rosacea, dermatitis,psoriasis and fungal disorders. According to an embodiment, the skindisease, disorder or condition is acne. According to another embodiment,the skin disease, disorder or condition is psoriasis.

In an embodiment, the present compositions are used in combination witha suitable additional pharmaceutical dosage form. The additionalpharmaceutical dosage form is administered to a patient either prior to,concomitantly with, or after the compositions described herein.

In one embodiment in this regard, the present composition and theadditional pharmaceutical dosage form are administered to a patient atthe same time. In an alternative embodiment, one of the presentcompositions and the additional pharmaceutical dosage form isadministered in the morning and the other is administered in theevening.

In another embodiment, the additional pharmaceutical dosage form can bea suitable oral pharmaceutical. In this regard, the present compositioncan be applied to the target area of the patient, prior to,concomitantly with, or after ingestion of the oral medication.

According to an embodiment, the present composition comprises a retinoidand the oral pharmaceutical dosage form comprises a pharmaceuticallyactive agent selected from the group consisting of an antibiotic, acontraceptive, a retinoid such as isotretioin, and a nutritional agent.

Furthermore, the foam compositions of the present invention may be usedwith other adjunct therapies and treatments, such as pre-washing withsoaps or cleansers. However, care is needed in this regard, sinceantibacterial soaps and abrasive soaps may increase irritation.

EXAMPLES

The following examples are illustrative of preferred embodiments hereinand are not to be construed as limiting the present invention thereto.All percentages are based on the percent by weight of the final deliverysystem or formulation prepared, unless otherwise indicated and alltotals equal 100% by weight.

Tables 2a, 2b, 2c and 2d Oil in Water Submicron/Micro Emulsion FoamFormulations—Tazarotene (0.1%)

TABLE 2a 706/8/2 - absent propellant* Component % w/w BHT 0.10 MacrogolCetostearyl Ether 12 5.00 (Ceteareth 12) Light Mineral Oil 6.00 SorbicAcid 0.40 DIPA 5.00 Tazarotene 0.10 Citric Acid Anhydrous 0.03 PotassiumCitrate 0.57 Monohydrate Deionized Water 82.80 Total 100.000

TABLE 2b 706/8/3 - absent propellant* Component % w/w BHT 0.10 MacrogolCetostearyl Ether 12 5.00 (Ceteareth 12) Light Mineral Oil 8.00 SorbicAcid 0.40 DIPA 7.00 Tazarotene 0.10 Citric Acid Anhydrous 0.03 PotassiumCitrate Monohydrate 0.54 Deionized Water 78.83 Total 100.000 *Theformulations described in Tables 2a & 2b were dispensed as a foamfollowing the addition of approximately 7 to 8 grams of AP70 propellantper 100 grams of aerosol base.*The formulations described in Tables 2a & 2b were dispensed as a foamfollowing the addition of approximately 7 to 8 grams of AP70 propellantper 100 grams of aerosol base.

TABLE 2c 730/2/1 Component Function % w/w % w/w BHT Antioxidant 0.1000.093 Macrogol Cetostearyl Ether 12 Surfactant 5.000 4.635 (Ceteareth12) Light Mineral Oil Oil 6.000 5.562 Sorbic Acid Preservative 0.1500.139 Potassium Sorbate Preservative 0.200 0.185 Diisopropyl adipateOrganic 5.000 4.635 Solvent Tazarotene Active 0.100 0.093 ingredientCitric Acid Anhydrous Buffer 0.037 0.034 Potassium Citrate Buffer 0.1030.096 Monohydrate Deionized Water Water 83.310 77.228 Propellant AP70(propane, Propellant — 7.300 butane & isobutane) Total 100.000 100.000

TABLE 2d SF10260-02 Component Function % w/w % w/w BHT Antioxidant 0.1000.093 Macrogol Cetostearyl Ether Surfactant 5.000 4.648 12 (Ceteareth12) Light Mineral Oil Oil 6.000 5.578 Sorbic Acid Preservative 0.1500.139 Potassium Sorbate Preservative 0.200 0.186 Diisopropyl adipateOrganic 5.000 4.648 Solvent Tazarotene Active 0.100 0.093 ingredientCitric Acid Anhydrous Buffer 0.037 0.034 Potassium Citrate Buffer 0.1030.096 Monohydrate Deionized Water Water 83.310 77.445 Propellant AP70(propane, Propellant — 7.040 butane & isobutane) Total 100.000 100.000

Example 1 Method of Preparing Submicron/Micro Emulsion FoamFormulation—Tazarotene

Procedure: aerosol base production (730/2/1):

-   -   Phase 1 (Oil phase): BHT, ceteareth-12, mineral oil and sorbic        acid    -   Phase 2 (Active phase): tazarotene dissolved in diisopropyl        adipate (DIPA)    -   Phase 3 (Buffer phase): deionized water (about 22.8% of the        total water content of aerosol base), citric acid, potassium        citrate and potassium sorbate    -   Phase 4 (Water phase): deionized water (about 77.2% of the total        water content of aerosol base)    -   1. Dissolve tazarotene in diisopropyl adipate in a suitable        stainless steel container at ambient temperature (Phase 2).    -   2. Prepare buffer solution at ambient temperature in a stainless        steel container (Phase 3).    -   3. Add oil phase ingredients to the main batch vessel (Phase 1).    -   4. Combine Phase 1, Phase 2 and Phase 3 in the main batch        vessel. Commence low heating with stirring. Continue heating to        the phase inversion temperature range of 70° C. to 80° C. until        a water in oil emulsion occurs.    -   5. Commence cooling to below the phase inversion temperature.        When the emulsion becomes an oil in water submicron/micro        emulsion, add ambient temperature Phase 4 deionized water at a        moderate rate. Stir until uniform. Maintain batch at 25° C.-30°        C.    -   6. Test pH of the aerosol base.    -   7. Adjust pH to a range of 4.70 to 5.50 with 1N potassium        hydroxide solution or with 10% citric acid solution.    -   8. Adjust to 100% with deionized water (to account for        evaporative water loss). The abovementioned procedure is        represented in schematic form in FIG. 1.

Alternative Procedure—Aerosol Base Production (SfW0260-02):

At ambient temperature, dissolve tazarotene in diisopropyl adipate in aside vessel, while stirring.

Add mineral oil and BHT to the side vessel, while stirring until thesolution is homogenous.

At ambient temperature, add deionized water (about 28.8% of total watercontent of aerosol base), citric acid and potassium citrate to a mainbatch vessel, while stirring until all components are fully dissolved.

Add potassium sorbate to the main batch vessel, while stirring until thepotassium sorbate is fully dissolved.

Continue to stir the contents of the main batch vessel and add thecontents of the side vessel (tazarotene, DIPA, mineral oil and BHT) tothe main batch vessel, followed by addition of sorbic acid andceteareth-12.

Commence heating and continue heating until the phase inversiontemperature is reached i.e. where the oil in water emulsion inverts to awater in oil emulsion (as measured by conductivity or visualobservation). The phase inversion temperature is in the range of about70° C. to about 80° C.

Cool the main batch vessel to below the phase inversion temperature(approximately 69° C.) to facilitate the formation of an oil in watersubmicron/micro emulsion.

Add ambient temperature deionized water (about 71.2% of total watercontent of aerosol base). Continue stirring and maintain main batchvessel at around 25° C.-30° C.

Test the pH and adjust as necessary to a range of 4.70 to 5.50. Adjustwith deionized water to account for evaporative water loss.

Aerosol Filling and Crimping

The aerosol base is filled into suitable aluminium aerosol containers,suitable valves are inserted, vacuum crimped and gassed with a suitablepropellant.

TABLE 3 Submicron/micro emulsion foam - tazarotene (0.1%) pluscalcipotriene (0.005%) Ingredient Function % w/w Item First active phase 1 Diisopropyl adipate Organic solvent 5.000  2 Tazarotene Activeingredient 0.100 Hydrocarbon oil phase  3 BHT Antioxidant 0.100  4Macrogol Cetostearyl Ether 12 Surfactant 5.000 (Ceteareth 12)  5 Mineraloil (light) Hydrocarbon 6.000  6 Tocopherol Antioxidant 0.002 Firstwater phase  7 Water (deionized) Aqueous solvent 19.000  8 EDTA, Na₂Buffer 0.060  9 Disodium phosphate Buffer 0.080 Second water phase 10Water (deionized) Aqueous solvent 54.653 Second active phase 11Propylene glycol Organic solvent 10.000 12 Calcipotriene Activeingredient 0.005 Total 100.000 Items Finished product 1 to 12 Aerosolbase Concentrate 92.7 13 Hydrocarbon propellant AP70 Propellant 7.3Total 100.0

Example 2 Method of Preparing Submicron/Micro Emulsion Foam—Tazarotene(0.1%) Plus Calcipotriene (0.005%) Aerosol Base:

-   -   1. Add BHT (Item 3), ceteareth-12 (Item 4), mineral oil (Item 5)        and tocopherol (Item 6) to the main mixing vessel.    -   2. Prepare the First active phase by adding diisopropyl adipate        (Item 1) and tazarotene (Item 2) to a small mixing vessel and        mix until tazarotene has dissolved.    -   3. Add the First active phase solution (Items 1 and 2) to the        main mixing vessel.    -   4. Into a separate mixing vessel prepare First water phase by        adding water (Item 7).    -   5. Start stirring First water phase and add EDTA, Na₂ (Item 8)        and disodium phosphate (Item 9) to water and mix until        dissolved.    -   6. Add First water phase (Items 7 to 9) to the main mixing        vessel.    -   7. While monitoring the conductivity of the contents of the main        mixing vessel (Items 1 to 9) commence heating, to approximately        80° C., and start stirring.    -   8. As the temperature increases the mixture inverts from an oil        in water emulsion to a water in oil emulsion and a corresponding        decrease in the conductivity is observed.    -   9. When the temperature reaches approximately 80° C. stop        heating and commence slow cooling of the contents of the main        mixing vessel while maintaining stirring.    -   10. At approximately 70° C. the mixture inverts from a water in        oil emulsion to an oil in water emulsion and a corresponding        increase in the conductivity is observed. The appearance of the        mixture also changes from opaque to translucent.    -   11. At this temperature, when the mixture is translucent, add        the Second water phase (Item 10), at ambient temperature, to the        main mixing vessel and continue stirring. The temperature of the        mixture will decrease to approximately 40° C. following the        addition of the Second water phase.    -   12. While stirring the mixture, continue cooling until the        temperature range decreases to approximately 25° C. to 30° C.    -   13. Prepare the Second active phase by adding propylene glycol        (Item 11) and calcipotriene (Item 12) to a small mixing vessel        and mix until calcipotriene has dissolved.    -   14. Transfer the Second active phase (Items 11 and 12) to the        main mixing vessel and stir until the mixture is uniform.

Finished Product:

1. Add Aerosol base (Items 1 to 12) to an empty aerosol container.2. Secure an aerosol valve onto the aerosol container.3. Add Propellant (Item 13) to the aerosol container.4. Test the aerosol container to confirm that there is no leakage.5. Place an actuator onto the aerosol valve.6. Shake the aerosol container prior to dispensing at room temperature.

TABLE 4 Submicron/micro emulsion foam - clindamycin phosphate (1%) plustretinoin (0.05%) Ingredient Function % w/w Item First active phase  1Diisopropyl adipate Organic solvent 10.000  2 Tretinoin Activeingredient 0.050 Hydrocarbon oil phase  3 BHT Antioxidant 0.100  4Macrogol Cetostearyl Ether 12 Surfactant 5.000 (Ceteareth 12)  5 Mineraloil (light) Hydrocarbon 6.000 First water phase  6 Water (deionized)Aqueous solvent 22.000  7 Anhydrous citric acid Buffer 0.037  8Potassium citrate monohydrate Buffer 0.103 Second water phase  9 Water(deionized) Aqueous solvent 32.960 Second active phase 10 Water(deionized) Aqueous solvent 20.000 11 Clindamycin phosphate (80% Activeingredient 1.250 active) Preservative phase 12 Propylene glycol 2.000 13Benzyl alcohol 0.500 Total 100.000 Items Finished product 1 to 13Aerosol base Concentrate 91.1 14 Hydrocarbon propellant AP70 Propellant8.9 Total 100.0

Example 3 Method of Preparing Submicron/Micro Emulsion FoamFormulation—Clindamycin Phosphate (1%) Plus Tretinoin (0.05%) AerosolBase:

-   -   1. Add BHT (Item 3), ceteareth-12 (Item 4) and mineral oil        (Item 5) to the main mixing vessel.    -   2. Prepare the First active phase by adding (Item 1) and        tretinoin (Item 2) to a small mixing vessel and mix until        dissolved.    -   3. Add the First active phase solution (Items 1 and 2) to the        main mixing vessel.    -   4. Into a separate mixing vessel prepare First water phase by        adding water (Item 6).    -   5. Start stirring First water phase and add anhydrous citric        acid (Item 7) and potassium citrate monohydrate (Item 8) to        water and mix until dissolved.    -   6. Add First water phase (Items 6 to 8) to the main mixing        vessel.    -   7. While monitoring the conductivity of the contents of the main        mixing vessel (Items 1 to 8) commence heating, to approximately        80° C., and start stirring.    -   8. As the temperature increases the mixture inverts from an oil        in water emulsion to a water in oil emulsion and a corresponding        decrease in the conductivity is observed.    -   9. After the mixture inverts from an oil in water emulsion to a        water in oil emulsion stop heating and commence slow cooling of        the contents of the main mixing vessel while maintaining        stirring.    -   10. With cooling, the mixture inverts from a water in oil        emulsion back to an oil in water emulsion and a corresponding        increase in the conductivity is observed. The appearance of the        mixture also changes from opaque to translucent.    -   11. At this temperature, when the mixture is translucent, add        the Second water phase (Item 9), at ambient temperature, to the        main mixing vessel and continue stirring. The temperature of the        mixture will decrease following the addition of the Second water        phase.    -   12. While stirring the mixture, continue cooling until the        temperature range decreases to approximately 25° C. to 30° C.    -   13. Prepare the Second active phase by adding water (Item 10)        and clindamycin phosphate (Item 11) to a small mixing vessel and        mix until clindamycin phosphate has dissolved.    -   14. Transfer the Second active phase (Items 10 and 11) to the        main mixing vessel and stir until the mixture is uniform.    -   15. Prepare the Preservative phase by adding propylene glycol        (Item 12) and benzyl alcohol (Item 13) to a small mixing vessel        and mix until uniform.    -   16. Transfer the Preservative phase (Items 12 and 13) to the        main mixing vessel and stir until the mixture is uniform.

Finished Product:

-   -   1. Add Aerosol base (Items 1 to 13) to an empty aerosol        container.    -   2. Secure an aerosol valve onto the aerosol container.    -   3. Add Propellant (Item 14) to the aerosol container.    -   4. Test the aerosol container to confirm that there is no        leakage.    -   5. Place an actuator onto the aerosol valve.    -   6. Shake the aerosol container prior to dispensing at room        temperature.        The formulations described in tables 5 to 9 are further        illustrative of the present invention.

TABLE 5 Submicron/micro emulsion foam - tazarotene (0.1%) plusclobetasol propionate (0.05%) Ingredient Function % w/w Item Firstactive phase  1 Diisopropyl adipate Organic solvent 5.000  2 TazaroteneActive ingredient 0.100 Hydrocarbon oil phase  3 BHT Antioxidant 0.100 4 Macrogol Cetostearyl Ether Surfactant 5.000 12 (Ceteareth 12)  5Mineral oil (light) Hydrocarbon 2.000  6 Sorbic acid Preservative 0.200 7 Petrolatum Hydrocarbon 2.000 First water phase  8 Water (deionized)Aqueous solvent 22.030  9 Anhydrous citric acid Buffer 0.040 10Potassium citrate Buffer 0.100 monohydrate 11 Potassium sorbatePreservative 0.270 Second water phase 12 Water (deionized) Aqueoussolvent 53.110 Second active phase 13 Propylene glycol Organic solvent10.000 14 Clobetasol propionate Active ingredient 0.050 Total 100.000Items Finished product 1 to 14 Aerosol base Concentrate 92.7 15Hydrocarbon propellant Propellant 7.3 AP70 Total 100.0

TABLE 6 Submicron/micro emulsion foam - Vitamin D3 (0.02%) IngredientFunction % w/w Item Active phase  1 Diisopropyl adipate Organic solvent2.000  2 Vitamin D3 Active ingredient 0.020 Hydrocarbon oil phase  3Macrogol Cetostearyl Ether Surfactant 3.000 12 (Ceteareth 12)  4 Mineraloil (light) Oil 3.000  5 Tocopherol Antioxidant 0.002 First water phase 6 Water (deionized) Aqueous solvent 10.000  7 Citric acid Buffer q.s. 8 Potassium citrate Buffer q.s. Second water phase  9 Water (deionized)Aqueous solvent to 100.000 10 Methyl paraben Preservative q.s. Total100.000 Items Finished product 1 to 10 Aerosol base Concentrate 92.7 11Hydrocarbon propellant Propellant 7.3 AP70 Total 100.0

TABLE 7 Submicron/micro emulsion foam - Salicylic acid (2%) IngredientFunction % w/w Item Active phase  1 Diisopropyl adipate Organic solvent9.000  2 Salicylic acid Active ingredient 2.000 Hydrocarbon oil phase  3Macrogol Cetostearyl Ether Surfactant 6.000 12 (Ceteareth 12)  4 Mineraloil (light) Oil 8.000 First water phase  5 Water (deionized) Aqueoussolvent 26.000  6 Citric acid Buffer q.s.  7 Potassium citrate Bufferq.s. Second water phase  8 Water (deionized) Aqueous solvent to 100.000 9 Benzyl alcohol Preservative q.s. Total 100.000 Items Finished product1 to 9 Aerosol base Concentrate 92.7 10 Hydrocarbon propellantPropellant 7.3 AP70 Total 100.0

TABLE 8 Submicron/micro emulsion foam - Adapalene 0.1% IngredientFunction % w/w Item Active phase  1 Diisopropyl adipate Organic solvent3.000  2 Adapalene Active ingredient 0.100 Hydrocarbon oil phase  3 BHTAntioxidant 0.100  4 Macrogol Cetostearyl Ether Surfactant 3.000 20(Ceteareth 20)  5 Mineral oil (light) Oil 4.000 First water phase  6Water (deionized) Aqueous solvent 15.000  7 Citric acid Buffer q.s.  8Potassium citrate Buffer q.s. Second water phase  9 Water (deionized)Aqueous solvent to 100.000 10 Benzyl alcohol Preservative q.s. Total100.000 Items Finished product 1 to 9 Aerosol base Concentrate 92.7 10Hydrocarbon propellant Propellant 7.3 AP70 Total 100.0

TABLE 9 Submicron/micro emulsion foam - clobetasol propionate (0.05%)Ingredient Function % w/w Item Active phase  1 Diisopropyl adipateOrganic solvent 5.00  2 Clobetasol propionate Active ingredient 0.05Hydrocarbon oil phase  3 Macrogol Cetostearyl Ether Surfactant 5.00 20(Ceteareth 20)  4 Mineral oil (light) Oil 5.00  5 BHT Antioxidant 0.10First water phase  6 Water (deionized) Water 20.00  7 Citric acid Bufferq.s.  8 Potassium citrate Buffer q.s. Second water phase  9 Water(deionized) Water to 100% 10 Methyl paraben Preservative q.s. Total100.00 Items Finished product 1 to 10 Aerosol base Concentrate 92.7 11Hydrocarbon propellant Propellant 7.3 AP70 Total 100.0

Example 4 Skin Penetration Study

A skin penetration study was performed, comparing the topical deliveryof the tazarotene submicron/micro emulsion foam (base) formulations ofExamples 2a and 2b to TAZORAC™ cream and gel formulations using in-vitroskin distribution assays.

Split-thickness skin (˜0.50 mm) sections were mounted in flow-throughdiffusion cells and test agents were applied at a finite dose of 15.63mg/cm² on 3 skin donors with 5 replicates each.

The tissues were collected at various time points (t=0, 2, 6 hrs),washed, tape stripped, and split into epidermis and dermis. Thedistribution of tazarotene within the epidermis, dermis, and wash werequantified by LC/MS/MS with a 50 pg/mL LOQ.

As shown in FIGS. 2 and 3, the skin penetration of the tazarotene foam(base) formulations in the epidermis and dermis was similar to thecommercial comparators (i.e. TAZORAC® cream and gel).

Example 5 Compatibility of Surfactants with Tazarotene

An accelerated stability study (using HPLC) was conducted at 50° C. tomeasure the compatibility of tazarotene with various surfactants. FIGS.4 and 5 show that tazarotene was most stable in a hydrophilicethoxylated fatty alcohol ether surfactant, such as Ceteareth—12, incontrast to various lipophilic surfactants.

Example 6 Measurement of Particle Size Distribution

The particle size distribution of the oil phase of the submicron/microemulsions (aerosol foam base) of the present invention was measuredusing a Malvern Mastersizer 2000 instrument. FIG. 6 illustrates theparticle size distribution of the oil phase of a preferred formulation(730/2/1). The mean particle size was 0.097 μm, that is, about 0.1 μm(i.e. about 100 nm).

1. An oil in water emulsion aerosol foam composition comprising an oilphase and a water phase, said composition comprising: i) tazarotene, ii)water, iii) an oil present in an amount of less than about 10% byweight, iv) an oil miscible organic solvent, v) a surfactant componentcomprising a hydrophilic surfactant, in an amount from about 0.1% toabout 10% by weight, and vi) a propellant; and wherein the tazarotene issolubilized in the oil phase of the composition, and the particle sizeof the oil phase is less than about 1000 nm, and wherein all percentagesare based on the total weight of the composition.
 2. The aerosol foamcomposition according to claim 1, wherein the composition comprises asecond pharmaceutically active agent.
 3. The aerosol foam compositionaccording to claim 1, wherein the composition comprises water in anamount from about 65% to about 90% by weight.
 4. The aerosol foamcomposition according to claim 3, wherein the composition compriseswater in an amount from about 70% to about 85% by weight.
 5. The aerosolfoam composition according to claim 1, wherein the oil is selected fromthe group consisting of azulene, chamazulene, isoparaffin, linear alphaolefins, cyclohexlidenediphenyl methane, didecene,diethylhexylcyclohexane, eicosane, isododecane, isoeicosane,isohexadecane, longifolene, mineral oil, paraffin, pentahydrosqualene,petrolatum, squalane, squalene, tetradecene, and mixtures thereof. 6.The aerosol foam composition according to claim 1, wherein the oil ispresent in an amount from about 1% to about 9% by weight.
 7. The aerosolfoam composition according to claim 6, wherein the oil is present in anamount from about 3% to about 8% by weight.
 8. The aerosol foamcomposition according to claim 7, wherein the oil is mineral oil.
 9. Theaerosol foam composition according to claim 1, wherein the oil miscibleorganic solvent is selected from the group consisting of diisopropyladipate, isopropyl myristate, octyl dodecanol and caprylic/caprictriglyceride, and mixtures thereof.
 10. The aerosol foam compositionaccording to claim 5, wherein the oil miscible organic solvent isselected from the group consisting of diisopropyl adipate, isopropylmyristate, octyl dodecanol and caprylic/capric triglyceride, andmixtures thereof.
 11. The aerosol foam composition according to claim10, wherein the oil is mineral oil.
 12. The aerosol foam compositionaccording to claim 1, wherein the surfactant component is present in anamount from about 1% to about 8% by weight.
 13. The aerosol foamcomposition according to claim 12, wherein the surfactant component ispresent in an amount from about 2% to about 6% by weight.
 14. Theaerosol foam composition according to claim 1, wherein the surfactantcomponent consists of a single hydrophilic surfactant.
 15. The aerosolfoam composition according to claim 1, wherein the surfactant componentcomprises two or more surfactants and the weighted average of the HLBvalue of the two or more surfactants is between about 10 and about 20.16. The aerosol foam composition according to claim 1, wherein thepropellant comprises one or more hydrocarbon propellants.
 17. A methodof treating a skin disease, disorder or condition, comprisingadministering to the skin of a patient requiring such treatment aneffective amount of a composition according to claim
 1. 18. An oil inwater emulsion aerosol foam composition comprising an oil phase and awater phase, said composition comprising: i) tazarotene; ii) water; iii)an oil selected from the group consisting of azulene, chamazulene,isoparaffin, linear alpha olefins, cyclohexlidenediphenyl methane,didecene, diethylhexylcyclohexane, eicosane, isododecane, isoeicosane,isohexadecane, longifolene, mineral oil, paraffin, pentahydrosqualene,petrolatum, squalane, squalene, tetradecene, and mixtures thereof; andwherein the oil is present in an amount from about 3% to about 8% byweight; iv) an oil miscible organic solvent selected from the groupconsisting of diisopropyl adipate, isopropyl myristate, octyl dodecanoland caprylic/capric triglyceride, and mixtures thereof; v) a non-ionicsurfactant component comprising a hydrophilic surfactant, in an amountfrom about 2% to about 6% by weight; vi) a hydrocarbon propellant; andwherein the tazarotene is solubilized in the oil phase of thecomposition, and wherein the particle size of the oil phase is less thanabout 1000 nm.
 19. A method of treating a skin disease, disorder orcondition, comprising administering to the skin of a patient requiringsuch treatment an effective amount of a composition according to claim18.
 20. A process for the preparation of an oil in water submicron ormicro emulsion aerosol foam composition, comprising tazarotene, water,an oil present in an amount of less than about 10% by weight, an oilmiscible organic solvent, a surfactant component comprising ahydrophilic surfactant in an amount from about 0.1% to about 10% byweight, and a propellant, the process comprising: a. admixing thetazarotene, a first aliquot of water, oil, oil miscible organic solventand surfactant component to form an oil in water emulsion, b. heatingthe oil in water emulsion of step (a) to a phase inversion temperaturewherein the oil in water emulsion forms a water in oil emulsion, c.cooling the water in oil emulsion to below the phase inversiontemperature to form a submicron or micro oil in water emulsion, d.adding a second aliquot of water to cool the submicron or micro oil inwater emulsion, and e. actuating a sample of the submicron or micro oilin water emulsion with a propellant to form an oil in water submicron ormicro emulsion aerosol foam.
 21. The process according to claim 20,wherein the first aliquot of water comprises about 10% to about 40% byweight of the total water content of the submicron or micro emulsionaerosol foam and the second aliquot of water comprises about 90% toabout 60% by weight of the total water content of the submicron or microemulsion aerosol foam.
 22. The product produced by the process accordingto claim
 20. 23. The aerosol foam composition according to claim 14,wherein the hydrophilic surfactant is selected from the group consistingof an ethoxylated fatty alcohol ether, a PEG derivative, an ethoxylatedfatty acid, a glyceryl ester derivative, a polymeric ether and asorbitan ester, and a mixture thereof.
 24. The aerosol foam compositionaccording to claim 15, wherein the two or more surfactants are non-ionicsurfactants selected from the group consisting of an ethoxylated fattyalcohol ether, a PEG derivative, an ethoxylated fatty acid, a propyleneglycol ester, a fatty alcohol, a glycerol ester or derivative thereof, apolymeric ether and a sorbitan ester, and a mixture thereof.
 25. Theaerosol foam composition according to claim 5, wherein the oil ismineral oil.
 26. The aerosol foam composition according to claim 9,wherein the oil miscible organic solvent is diisopropyl adipate.